A Plasminogen Activator Inhibitor (PAI-2) Circulates in Two Molecular Forms During Pregnancy

Summary

During normal pregnancy maternal haemostasis alters to protect against bleeding with a rise in plasma clotting factor levels and increased inhibition of fibrinolysis. The latter is due in part to increased levels of the 48 kDa plasminogen activator inhibitor (PAI-1) present in the plasma of non-pregnant individuals. A second plasminogen activator inhibitor (PAI-2) occurs in placenta and in a cultured histiocytic lymphoma cell line. We report here the identification by SDS-PAGE and zymography of PAI-2 in plasma during normal pregnancy. PAI-2 was present in two molecular forms of about 75 and 130 kDa, which were detectable at 12 weeks gestation and which persisted in the maternal circulation for up to 7 days after delivery. These forms of PAI-2 appear to be distinct from purifed PAI-2, which has a molecular mass of 47–60 kDa and which is not normally detectable in this zymographic system, since it is sensitive to denaturants. The novel forms of PAI-2 may represent complexes or aggregates that retain activity after SDS-PAGE.

Keywords

Plasminogen activator inhibitor - Pregnancy - Inhibition of fibrinolysis

• References

• 1 Bonnar J, McNicol GP, Douglas AS. Coagulation and fibrinolytic mechanism during and after normal childbirth. Br Med J 1970; 2: 200-203
• 2 Stirling Y, Woolf L, North W RS, Seghatchian MJ, Meade TW. Haemostasis in normal pregnancy. Thromb Haemostas 1984; 52: 176-182
• 3 Bonnar J, McNicol GP, Douglas AS. Fibrinolytic enzyme system and pregnancy. Br Med J 1969; 3: 387-388
• 4 Brakman P, Astrup T. Selective inhibition in human pregnancy blood of urokinase induced fibrinolysis. Scand J Clin Lab Invest 1963; 15: 603-609
• 5 Walker JE, Gow L, Campbell DM, Ogston D. The inhibition by-plasma of urokinase and tissue activator-induced fibrinolysis in pregnancy and the puerperium. Thromb Haemostas 1983; 49: 21-23
• 6 Cohen D. Report of the meeting of the subcommittee on fibrinolysis. Jerusalem. Israel, June 2. 1986. Thromb Haemostas 1986; 56: 415-416
• 7 Sprengers ED, Kluft C. Plasminogen activator inhibitors. Blood 1987; 69: 381-387
• 8 Kawano T, Morimoto K, Uemura Y. Urokinase inhibitor in human placenta. Nature 1968; 217: 253-254
• 9 Lecander I, Roblin R, Astedt B. Differential inhibition of two molecular forms of melanoma cell plasminogen activator by a placental inhibitor. Br J Haematol 1984; 57: 407-412
• 10 Kruithof E KO, Vassalli JD, Schleuning WD, Mattaliano RJ, Bachmann F. Purification and characterization of a plasminogen activator inhibitor from the histiocvtic lymphoma cell line U-937. J Biol Chem 1986; 261: 11207-11213
• 11 Loskutoff DJ, van J AMourik, Erickson LA, Lawrence D. Detection of an unusually stable fibrinolytic inhibitor produced by bovine endothelial cells. Proc Natl Acad Sci USA 1983; 80: 2956-2960
• 12 Erickson LA, Ginsberg MH, Loskutoff DJ. Detection and partial characterization of an inhibitor of plasminogen activator in human platelets. J Clin Invest 1984; 74: 1465-1472
• 13 Booth NA, Anderson JA, Bennett B. Platelet release protein which inhibits plasminogen activators. J Clin Pathol 1985; 38: 825-830
• 14 Erickson LA, Hekman CM, Loskutoff DJ. The primary plasminogen activator inhibitors in endothelial cells, platelets, serum, and plasma are immunologicaliy related. Proc Natl Acad Sci USA 1985; 82: 8710-8714
• 15 Booth NA, Anderson JA, Bennett B. The plasma inhibitors of plasminogen activator, studied by a zymographic technique. Thromb Res 1985; 38: 261-267
• 16 Booth NA, MacGregor IR, Hunter NR, Bennett B. Plasminogen activator inhibitor from human endothelial cells ; purification and partial characterization. Eur J Biochem 1987; 165: 595-600
• 17 Booth NA, Bennett B. Plasmin-a₂-antiplasmin complex as an indicator of in vivo fibrinolysis. Br J Haematol 1982; 50: 537-541
• 18 Kruithof E KO, Tran-Thang C, Gudinchet A, Hauert J, Nicoloso G, Genton C, Welti H, Bachmann F. Fibrinolysis in pregnancy. A study of plasminogen activator inhibitors. Blood 1987; 69: 460-466
• 19 Holmberg L, Lecander I, Persson B, Astedt B. An inhibitor from placenta specifically binds urokinase and inhibits plasminogen activator released from ovarian carcinoma in tissue culture. Biochim Biophys Acta 1978; 544: 128-137
• 20 Lecander I, Astedt B. Isolation of a new specific plasminogen activator inhibitor from pregnancy plasma. Br J Haematol 1986; 62: 221-228
• 21 Uszynski M, Abildgaard U. Separation and characterization of two fibrinolytic inhibitors from human placenta. Thrombos Diathes Haemorrh 1971; 25: 580-589
• 22 Cajot JF, Kruithof E KO, Schleuning WD, Sordat B, Bachmann F. Plasminogen activators, plasminogen activator inhibitors and procoagulant analyzed in twenty human tumor lines. Int J Cancer 1986; 38: 719-727